Background: TP53-mutated (TP53^mut) acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) are often treated with hypomethylating agents (HMAs) in combination with Venetoclax (Ven), however, myelosuppression from treatment leads to frequent dose-reductions and/or cycle delays. An approach to decrease HMA-mediated myelosuppression while maintaining S-phase dependent DNMT1-targeting is to administer noncytotoxic doses of Decitabine (Dec) by a frequent-distributed schedule of 1X/week. In pre-clinical studies Ven given as a single dose prior to HMA administration has been shown to inhibit de novo pyrimidine synthesis and counter a major mechanism of resistance to HMAs in MDS/AML, without suppressing normal myelopoiesis. Methods: We conducted a retrospective analysis of all pts with TP53^mut MDS/AML at our institution treated with weekly Ven 400mg on D1 and low-dose subcutaneous (subQ) Dec (0.2 mg/kg; ̃5 mg/m²) on D2, administered weekly in 28 day cycles. We analyzed patient characteristics, response to therapy, and outcomes using standard descriptive statistics. Results: Six pts with TP53^mut MDS or AML were treated. Two pts with high-risk MDS and 3 pts with adverse risk AML (83%) received treatment frontline, all with poor performance status (PS), and 1 pt (17%) had R/R MDS transformed to adverse risk AML refractory to both standard Aza/Ven and Vyxeos. Median age at diagnosis was 79 years [41-82]. Median TP53^mut variant allelic frequency (VAF) was 48% [28-79]. Cytogenetics were complex in all pts. Median follow-up was 10.1 months (mo) [2.9-16.3] and 83% pts were transfusion dependent prior to treatment. Overall response rate (ORR) was 100%: 5/5 frontline pts had complete remissions (CR), and the 1 R/R pt achieved a morphologic leukemia-free state. Median time to best response was 2.5 mo and 60% pts became transfusion independent. 33% pts lost their TP53^mut at best response, and another 50% pts had significant reductions (83%, 46% and 38%) in TP53^mut VAF. The regimen was well tolerated with no pts stopping therapy due to adverse effects, with a median of 1.5 unplanned hospitalizations per pt during follow-up. Median duration of therapy was 13.8 mo [6.1-27.1] with 2 (33%) pts remaining on therapy and 2 (33%) pts with measurable relapse who have since died. One pt underwent allogeneic stem cell transplantation, however, died 11.4 mo after conditioning due to transplant related mortality. The R/R pt died after being lost to follow-up 2.9 mo after therapy initiation. Conclusions: Combination weekly Ven with low-dose subQ Dec is well tolerated yielding high rates of clinical and molecular response in pts with TP53^mut MDS/AML. Although small, this case-series extends proof-of-activity of non-cytotoxic DNMT1-targeting to a high-risk, poor PS, historically chemorefractory patient population allowing frequent, sustained drug exposure often not possible with standard HMA/Ven regimens.